Despite the success of antiretroviral (ARV) prophylaxis to prevent vertical HIV-1 transmission, more than 150,000 infants acquired HIV-1 in 2015. These infant infections are partly due to suboptimal HIV-1 testing and ARV coverage in areas with high HIV-1 incidence. Yet, even if 90% ARV coverage is achieved for pregnant women known to be infected with HIV-1 globally, it is estimated that more than 100,000 infants will still become infected with HIV-1 annually. This is due to several settings in which suppressive antiretroviral therapy may not be achieved or diagnosis of maternal infection may not be timely, including: (i) acute infection of the mother during pregnancy or breastfeeding, (ii) late presentation to prenatal care, (iii) maternal non-adherence, which can be particularly challenging for the full duration of breastfeeding, and (iv) the development of drug-resistant variants. Thus, there remains a critical need to develop easy-to-implement immune-based prophylaxis strategies to prevent infant HIV-1 acquisition, such as infant HIV-1 immunization. Investigators in the HIV Vaccine Trials Network (HVTN) and the International Maternal Pediatric Adolescent AIDS Clinical Trials Network (IMPAACT) are planning a phase 1 clinical trial to evaluate the safety and immunogenicity of the HIV-1 CH505 transmitted/founder (T/F) ENV vaccine in healthy, HIV-exposed infants. Extracting the greatest insights from study clinical specimens will require a robust approach to systems vaccinology data on the small cohort of infant vaccinees. This will allow the greatest possible detail in comparing infant to adult responses.